Repurposing of FDA-approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID-19 Main Protease

Abstract

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

Integrated bioinformatics–cheminformatics approach toward locating pseudo‐potential antiviral marine alkaloids against SARS‐CoV‐2‐Mpro

“…Similarly, p‐gp is another factor associated with drug distribution across the cell membrane/efflux‐membrane transporter, directly linked to optimal drug delivery 51,52 . Overall, the computational prediction has reduced the resource and cost of selecting ideal lead candidates by filtering the essential drug parameters 52–55 . Concludingly, this cost‐effective, resource‐saving, and highly efficient computational screening is helpful to locate several repurposing candidates like marine alkaloids toward control of gruesome SARS‐CoV in this health emergency.…”

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

“…From the above discussion, it can be suggested that this new quantity can be employed to identify and select an optimum set of flexible residues in the binding site for induced-fit docking (IFD) and flexible docking methods. 43,46,65,66 Based on this quantity and the values reported in Figure 2, despite the relative importance of some residues in the binding site like Cys145 and Gly143 which have contacts with the ligands in most of the complexes, around 84% and 73%, respectively, are highly rigid residues and should be removed from a set of flexible residues during IFD simulations, which is significant for achieving optimal performance of IFD protocols and saving the computation time. Moreover, it is clear from the values of residue flexibility in Figure 2 that the segment Gly143-Cys145 which defines the "oxyanion hole" as an essential part of the substrate-binding pocket represents considerable structural rigidity, in agreement with computational observations.…”

“…Finally, as an interesting case, Ser144 which interacts with its ligands in ~58.2% of the complexes is the most rigid residue for which there are only two RMSD matrix elements with values of more than 1.0 Å (0.01% of the RMSD matrix elements), and therefore, this residue has a similar configuration in almost all studied complexes. From the above discussion, it can be suggested that this new quantity can be employed to identify and select an optimum set of flexible residues in the binding site for induced‐fit docking (IFD) and flexible docking methods 43,46,65,66 . Based on this quantity and the values reported in Figure 2, despite the relative importance of some residues in the binding site like Cys145 and Gly143 which have contacts with the ligands in most of the complexes, around 84% and 73%, respectively, are highly rigid residues and should be removed from a set of flexible residues during IFD simulations, which is significant for achieving optimal performance of IFD protocols and saving the computation time.…”

Bromocriptine therapy: Review of mechanism of action, safety and tolerability

“…Recent studies on computer‐aided drug screening showed that bromocriptine probably inhibits the SARS‐CoV‐2 replication by exhibiting high binding affinity for both viral RNA‐dependent RNA polymerase and SARS‐CoV‐2 3C‐like protease enzymes 369,370 . Because bromocriptine is widely used clinically as well for a variety of other diseases with high safety profile and cost‐effectiveness, they repurposed it either alone or as an adjuvant with other currently used therapies in the treatment of COVID‐19 371–374 . Moreover, low dose bromocriptine administration has been seen to be fruitful in COVID‐19 patients presenting with NMS and various other central nervous system and endocrine system symptoms 372,375 …”

“…369,370 Because bromocriptine is widely used clinically as well for a variety of other diseases with high safety profile and cost-effectiveness, they repurposed it either alone or as an adjuvant with other currently used therapies in the treatment of COVID-19. [371][372][373][374] Moreover, low dose bromocriptine administration has been seen to be fruitful in COVID-19 patients presenting with NMS and various other central nervous system and endocrine system symptoms. 372,375…”